Angiotensin II (All) is a critical regulator of cardiovascular homeostasis. Recent data suggest an important role for the angiotensin II type I receptor (AT I R) as the mediator of All effects on cell function that are pathogenic for hypertension, atherosclerosis, and congestive heart failure. Thus, the major goal of this proposal is to understand All pathogenic mechanisms by defining the vascular smooth muscle cell (VSMC) specific signal transduction events activated by the AT I R. A critical clinical and basic question has been to understand the mechanisms by which All causes pleiotropic effect such as contraction, growth, inhibition of apoptosis, and migration. The applicant proposes that c-Src mediates many of the non-growth related effects of All in VSMC, namely protein synthesis, migration, protection from apoptosis and focal adhesion signaling. Using retrovirally transduced VSMC which express DN-Src or VSMC from transgenic c-Src deficient mice significant inhibition of All-mediated signal transduction, such as activation of Extracellular signal-Regulated Kinase 1/2 (ERK 1/2) and tyrosine phosphorylation of the focal adhesion proteins p 13OCas, paxillin, and tensin was observed. However, All stimulation of c-jun N-terminal kinase, p7O S6 kinase, and protein synthesis in VSMC is independent of c-Src. These finding support the hypothesis that c-Src is responsible for the non-growth signals activated by All in VSMC. Determining the signal pathways by which the ATIR activates c-SRC should provide insights into the nature of G protein coupled receptor function and how All regulates VSMC function. The following specific aims are proposed. Characterize the AII stimulated events in VSMC that require c-Src. Aim 2: determine the role of Rho family G proteins in activation of c-Src AII. Aim 3: Study the role of PDGF receptor tyrosine phosphorylation in fine domains of the AT I R required knowledge of the mechanisms by which AII exerts physiologic and pathologic effects on the cardiovascular system.